Prostacyclin prevents murine lung cancer independent of the membrane receptor by activation of PPARγ

Overexpression of prostacyclin synthase (PGIS) decreases lung tumor multiplicity in chemical and cigarette-smoke induced murine lung cancer models. Prostacyclin signals through a single G-protein coupled receptor (IP), which signals through cAMP. To determine the role of this receptor in lung cancer chemoprevention by prostacyclin, PGIS-overexpressing mice were crossed to mice that lack the IP receptor (IP (−/−)). Carcinogen-induced lung tumor incidence was similar in IP(+/+), IP(+/−) and IP(−/−) mice, and overexpression of PGIS gave equal protection in all three groups, indicating that the protective effects of prostacyclin are not mediated through activation of IP. Since prostacyclin can activate members of the PPAR family of nuclear receptors, we examined the role of PPARγ in prostacyclin’s protection against lung tumorigenesis. Iloprost, a stable prostacyclin analog, activated PPARγ in non-transformed bronchial epithelial cells and in a subset of human non-small cell lung cancer cell lines (NSCLC). Iloprost-impregnated chow fed to wild-type mice resulted in elevated lung macrophages and decreased lung tumor formation. Transgenic animals with lung specific PPARγ-overexpression also developed fewer lung tumors. This reduction was not enhanced by administration of supplemental iloprost. These studies indicate that PPARγ is a critical target for prostacyclin mediated lung cancer chemoprevention, and may also have therapeutic activity.